Mutations In Connexin Research Articles

Long-term hybridization in a karst window reveals the genetic basis of eye loss in cavefish.

Eye loss is a hallmark trait of animals inhabiting perpetual darkness, such as caves. The Mexican tetra ( Astyanax mexicanus) provides an unparalleled model for studying the genetic basis of eye loss. There are two interfertile morphs of the Mexican tetra, sighted surface fish and multiple independently evolved eyeless, blind cavefish populations. Despite decades of research on eye loss in this species, our understanding of the precise genetic basis remains sparse. Here, we focused on the unique Caballo Moro cave, where there is a karst window collapse that introduced sunlight and coexistence of both eyed and eyeless cavefish of similar genetic background. This unique genetic mosaic allowed us to pinpoint coding mutations in Connexin 50 (Cx50), also known as gap junction protein alpha 8b (Gja8b), as critical in the genetic basis of eye loss. CRISPR based knockouts of Cx50 in surface fish result in small or absent eyes as young as 48 hours post-fertilization. Further, we identified similar mutations in Cx50 that alter predicted protein structure among other cave-dwelling fish and even subterranean mammals, indicating a conserved evolutionary mechanism of Cx50 mutations. We introduced a mutation (Cx50-S89K) in mice, which resulted in cataracts, smaller eyes, and smaller lenses. Mutations in Cx50 mimic those identified in human congenital cataracts. We additionally leveraged phenotypic variation in a hybrid cavefish population to demonstrate that eyes provide fish with a metabolic advantage, providing a mechanism by which loss of eyes could be favored by selection. This unique hybridization event allowed us to identify novel alleles that contribute to the convergent evolution of eye loss, providing profound insights into the genetic underpinnings of one of nature's most fascinating adaptive traits.

Large-pore connexin hemichannels function like molecule transporters independent of ion conduction

Connexin hemichannels were identified as the first members of the eukaryotic large-pore channel family that mediate permeation of both atomic ions and small molecules between the intracellular and extracellular environments. The conventional view is that their pore is a large passive conduit through which both ions and molecules diffuse in a similar manner. In stark contrast to this notion, we demonstrate that the permeation of ions and of molecules in connexin hemichannels can be uncoupled and differentially regulated. We find that human connexin mutations that produce pathologies and were previously thought to be loss-of-function mutations due to the lack of ionic currents are still capable of mediating the passive transport of molecules with kinetics close to those of wild-type channels. This molecular transport displays saturability in the micromolar range, selectivity, and competitive inhibition, properties that are tuned by specific interactions between the permeating molecules and the N-terminal domain that lies within the pore-a general feature of large-pore channels. We propose that connexin hemichannels and, likely, other large-pore channels, are hybrid channel/transporter-like proteins that might switch between these two modes to promote selective ion conduction or autocrine/paracrine molecular signaling in health and disease processes.

Genetically engineered human embryonic kidney cells as a novel vehicle for dual patch clamp study of human gap junction channels.

Mutations in more than half of human connexin genes encoding gap junction (GJ) subunits have been linked to inherited human diseases. Functional studies of human GJ channels are essential for revealing mechanistic insights into the etiology of disease-linked connexin mutants. However, the commonly used Xenopus oocytes, N2A, HeLa, and other model cells for recombinant expression of human connexins have different and significant limitations. Here we developed a human cell line (HEK293) with each of the endogenous connexins (Cx43 and Cx45) knocked out using the CRISPR-Cas9 system. Double knockout HEK293 cells showed no background GJ coupling, were easily transfected with several human connexin genes (such as those encoding Cx46, Cx50, Cx37, Cx45, Cx26, and Cx36) which successfully formed functional GJs and were readily accessible for dual patch clamp analysis. Single knockout Cx43 or Cx45 HEK cell lines could also be used to characterize human GJ channels formed by Cx45 or Cx43, respectively, with an expression level suitable for studying macroscopic and single channel GJ channel properties. A cardiac arrhythmia linked Cx45 mutant R184G failed to form functional GJs in DKO HEK293 cells with impaired localizations. These genetically engineered HEK293 cells are well suited for patch clamp study of human GJ channels.

Connexins in epidermal health and diseases: insights into their mutations, implications, and therapeutic solutions.

The epidermis, the outermost layer of the skin, serves as a protective barrier against external factors. Epidermal differentiation, a tightly regulated process essential for epidermal homeostasis, epidermal barrier formation and skin integrity maintenance, is orchestrated by several players, including signaling molecules, calcium gradient and junctional complexes such as gap junctions (GJs). GJ proteins, known as connexins facilitate cell-to-cell communication between adjacent keratinocytes. Connexins can function as either hemichannels or GJs, depending on their interaction with other connexons from neighboring keratinocytes. These channels enable the transport of metabolites, cAMP, microRNAs, and ions, including Ca2+, across cell membranes. At least ten distinct connexins are expressed within the epidermis and mutations in at least five of them has been linked to various skin disorders. Connexin mutations may cause aberrant channel activity by altering their synthesis, their gating properties, their intracellular trafficking, and the assembly of hemichannels and GJ channels. In addition to mutations, connexin expression is dysregulated in other skin conditions including psoriasis, chronic wound and skin cancers, indicating the crucial role of connexins in skin homeostasis. Current treatment options for conditions with mutant or altered connexins are limited and primarily focus on symptom management. Several therapeutics, including non-peptide chemicals, antibodies, mimetic peptides and allele-specific small interfering RNAs are promising in treating connexin-related skin disorders. Since connexins play crucial roles in maintaining epidermal homeostasis as shown with linkage to a range of skin disorders and cancer, further investigations are warranted to decipher the molecular and cellular alterations within cells due to mutations or altered expression, leading to abnormal proliferation and differentiation. This would also help characterize the roles of each isoform in skin homeostasis, in addition to the development of innovative therapeutic interventions. This review highlights the critical functions of connexins in the epidermis and the association between connexins and skin disorders, and discusses potential therapeutic options.

Measurement of Ca2+ Uptake Through Connexin Hemichannels.

Increasing evidence points to deregulated flux of ionized calcium (Ca2+) mediated by hyperactive mutant connexin (Cx) hemichannels (HCs) as a common gain-of-function etiopathogenetic mechanism for several diseases, ranging from skin disorders to nervous system defects. Furthermore, the opening of nonmutated Cx HCs is associated with an impressive list of widespread diseases including, but not limited to, ischemia/stroke, Alzheimer's disease, and epilepsy. HC inhibitors are attracting a growing attention due to their therapeutic potential for numerous pathologies. This chapter describes a quantitative method to measure Ca2+ uptake though HCs expressed in cultured cells. The assay we developed can be used to probe HC activity as wells as to test HC inhibitors. Furthermore, with minor changes it can be easily adapted to high-throughput high-content platforms and/or primary cells and microtissues.

Purification, Reconstitution, and Functional Analysis of Connexin Hemichannels.

Connexins are the proteins that form the gap junction channels that are essential for cell-to-cell communication. These channels are formed by head-to-head docking of hemichannels (each from one of two adjacent cells). Free "undocked" hemichannels at the plasma membrane are mostly closed, although they are still important under physiological conditions. However, abnormal and sustained increase in hemichannel activity due to connexin mutations or acquired conditions can produce or contribute to cell damage. For example, mutations of Cx26, a connexin isoform, can increase hemichannel activity andcause deafness. Studies using purified isolated systems under well-controlled conditions are essential for a full understanding of molecular mechanisms of hemichannel function under normal conditions and in disease, and here, we present methodology for the expression, purification, and functional analysis of hemichannels formed by Cx26.

Structures of wild-type and selected CMT1X mutant connexin 32 gap junction channels and hemichannels.

In myelinating Schwann cells, connection between myelin layers is mediated by gap junction channels (GJCs) formed by docked connexin 32 (Cx32) hemichannels (HCs). Mutations in Cx32 cause the X-linked Charcot-Marie-Tooth disease (CMT1X), a degenerative neuropathy without a cure. A molecular link between Cx32 dysfunction and CMT1X pathogenesis is still missing. Here, we describe the high-resolution cryo-electron cryo-myography (cryo-EM) structures of the Cx32 GJC and HC, along with two CMT1X-linked mutants, W3S and R22G. While the structures of wild-type and mutant GJCs are virtually identical, the HCs show a major difference: In the W3S and R22G mutant HCs, the amino-terminal gating helix partially occludes the pore, consistent with a diminished HC activity. Our results suggest that HC dysfunction may be involved in the pathogenesis of CMT1X.

The Role of Gap Junctions Dysfunction in the Development of Cataracts: From Loss of Cell-to-Cell Transfer to Blurred Vision-Review.

Mutations of lens connexins are linked to congenital cataracts. However, the role of connexin mutations in the development of age-related lens opacification remains largely unknown. Here, we present a focused review of the literature on lens organization and factors associated with cataract development. Several lines of evidence indicate that disturbances of the lens circulation by dysfunctional connexin channels, and/or accumulation of protein damage due to oxidative stress, are key factors in cataract development. Phosphorylation by protein kinase A improves the permeability of connexins channels to small molecules and mitigates the lens clouding induced by oxidative stress. We conclude (1) that connexin channels are central to the lens circulation and (2) that their permeability to antioxidant molecules contributes to the maintenance of lens transparency.

Inherited disease-linked arginine76/75 mutants in Cx50 and Cx45 showed impaired homotypic and heterotypic gap junction function, but not Cx43.

Connexins form intercellular communication channels, known as gap junctions (GJs), in many tissues/organs. Mutations in connexin genes are found to be linked to various inherited diseases, but the mechanisms are not fully clear. The Arg76 (R76) in Cx50 is fully conserved across the entire connexin family and is a hotspot for five connexin-linked inherited diseases, including Cx50 and Cx46-linked congenital cataract, Cx43-linked oculodentodigital dysplasia, and Cx45-linked cardiac arrhythmias. To better understand the molecular and cellular mechanism of dysfunction caused by R76/75 mutations, we examined the functional status and properties of GJs containing R76 mutations in Cx50 (R76H/C), Cx43 (R76H/S/C), and Cx45 (R75H) with an emphasis on heterotypic GJs in connexin-deficient model cells. All tested mutants showed an impairment of homotypic GJ function reflected by a decreased coupling% and conductance, except for Cx43 R76H/S. These connexin mutants also showed impaired GJ function when paired with a docking compatible connexin, such as Cx50/Cx46 or Cx45/Cx43, except for all mutants on Cx43 which formed functional heterotypic GJs with Cx45. Localization studies on fluorescent protein tagged connexin mutants revealed that Cx45 R75H and Cx43 R76C showed impaired localization. Our homology structure models indicated that mutations of R76/75 in these GJs led to a loss of intra- and/or inter-connexin non-covalent interactions (salt bridges) at the sidechain of this residue, which could contribute to the observed GJ impairments underlying diseases. It is interesting that unlike those disease-linked variants in Cx50 and Cx45, Cx43 can tolerate some variations at R76.

Cytomembrane Trafficking Pathways of Connexin 26, 30, and 43.

The connexin gene family is the most prevalent gene that contributes to hearing loss. Connexins 26 and 30, encoded by GJB2 and GJB6, respectively, are the most abundantly expressed connexins in the inner ear. Connexin 43, which is encoded by GJA1, appears to be widely expressed in various organs, including the heart, skin, the brain, and the inner ear. The mutations that arise in GJB2, GJB6, and GJA1 can all result in comprehensive or non-comprehensive genetic deafness in newborns. As it is predicted that connexins include at least 20 isoforms in humans, the biosynthesis, structural composition, and degradation of connexins must be precisely regulated so that the gap junctions can properly operate. Certain mutations result in connexins possessing a faulty subcellular localization, failing to transport to the cell membrane and preventing gap junction formation, ultimately leading to connexin dysfunction and hearing loss. In this review, we provide a discussion of the transport models for connexin 43, connexins 30 and 26, mutations affecting trafficking pathways of these connexins, the existing controversies in the trafficking pathways of connexins, and the molecules involved in connexin trafficking and their functions. This review can contribute to a new way of understanding the etiological principles of connexin mutations and finding therapeutic strategies for hereditary deafness.

A crystallin mutant cataract with mineral deposits

Connexin mutant mice develop cataracts containing calcium precipitates. To test whether pathologic mineralization is a general mechanism contributing to the disease, we characterized the lenses from a nonconnexin mutant mouse cataract model. By cosegregation of the phenotype with a satellite marker and genomic sequencing, we identified the mutant as a 5-bp duplication in the γC-crystallin gene (Crygcdup). Homozygous mice developed severe cataracts early, and heterozygous animals developed small cataracts later in life. Immunoblotting studies showed that the mutant lenses contained decreased levels of crystallins, connexin46, and connexin50 but increasedlevels of resident proteins of the nucleus, endoplasmic reticulum, and mitochondria. The reductions in fiber cell connexins were associated with a scarcity of gap junction punctae as detected by immunofluorescence and significant reductions in gap junction-mediated coupling between fiber cells in Crygcdup lenses. Particles that stained with the calcium deposit dye, Alizarin red, were abundant in the insoluble fraction from homozygous lenses but nearly absent in wild-type and heterozygous lens preparations. Whole-mount homozygous lenses were stained with Alizarin red in the cataract region. Mineralized material with a regional distribution similar to the cataract was detected in homozygous lenses (but not wild-type lenses) by micro-computed tomography. Attenuated total internal reflection Fourier-transform infrared microspectroscopy identified the mineral as apatite. These results are consistent with previous findings that loss of lens fiber cell gap junctional coupling leads to the formation of calcium precipitates. They also support the hypothesis that pathologic mineralization contributes to the formation of cataracts of different etiologies.

A Chemical Chaperone Restores Connexin 26 Mutant Activity.

Mutations in connexin 26 (Cx26) cause hearing disorders of a varying degree. Herein, to identify compounds capable of restoring the function of mutated Cx26, a novel miniaturized microarray-based screening system was developed to perform an optical assay of Cx26 functionality. These molecules were identified through a viability assay using HeLa cells expressing wild-type (WT) Cx26, which exhibited sensitivity toward the HSP90 inhibitor radicicol in the submicromolar concentration range. Open Cx26 hemichannels are assumed to mediate the passage of molecules up to 1000 Da in size. Thus, by releasing radicicol, WT Cx26 active hemichannels in HeLa cells contribute to a higher survival rate and lower cell viability when Cx26 is mutated. HeLa cells expressing Cx26 mutations exhibited reduced viability in the presence of radicicol, such as the mutants F161S or R184P. Next, molecules exhibiting chemical chaperoning activity, suspected of restoring channel function, were assessed regarding whether they induced superior sensitivity toward radicicol and increased HeLa cell viability. Through a viability assay and microarray-based flux assay that uses Lucifer yellow in HeLa cells, compounds 3 and 8 were identified to restore mutant functionality. Furthermore, thermophoresis experiments revealed that only 3 (VRT-534) exhibited dose-responsive binding to recombinant WT Cx26 and mutant Cx26K188N with half maximal effective concentration values of 19 and ∼5 μM, respectively. The findings of this study reveal that repurposing compounds already being used to treat other diseases, such as cystic fibrosis, in combination with functional bioassays and binding tests can help identify novel potential candidates that can be used to treat hearing disorders.

Intraoperative Neural Response Telemetry and Auditory Outcomes in Pediatric Cochlear Implantation.

To evaluate the relationship between intraoperative neural response telemetry (NRT) and postoperative auditory testing outcomes in children. Retrospective study. Tertiary-care academic center. Children who underwent cochlear implantation using the Cochlear Corporation device between 2010 and 2019 were included. Associations of average NRT and the slope of amplitude with postoperative auditory outcomes including functional auditory measure Infant-Toddler Meaningful Auditory Integration Scale (IT-MAIS), and speech perception testing (consonant-nucleus-consonant [CNC], Pediatric AzBio [BABY BIO], Hearing In Noise Test [HINT], and Northwestern University Children's Perception of Speech [NU-CHIPS]), measured between 6 and 57 months after implantation, were assessed using Spearman's rank correlation (ρ). Thirty-eight patients (19 female, 19 male) and 54 ears were included. The median age of implantation was 20.6 months (range 9.6 months to 10.6 years). Eight (21%) children had neurologic disorders such as stroke, epilepsy, cerebral palsy, and other causes. Thirteen (34%) children had connexin mutations. Average NRT was not significantly correlated with postoperative auditory outcomes (IT-MAIS [ρ = -0.08, p = .74], CNC [ρ = 0.19, p = .32], BABY BIO [ρ = 0.21, p = .29], HINT [ρ = 0.05, p = .83])and NU-CHIPS (ρ = 0.21, p = .28). The average slopes of amplitude and comfort level were not strongly correlated with any auditory outcomes (p > .05). Intraoperative NRT was not correlated with any postoperative functional auditory outcomes. Patient counseling should include discussions that a subpar intraoperative cochlear response does not preclude favorable speech and auditory outcomes.

Inherited disease-linked arginine76 or equivalent residue mutants in Cx50 and Cx45 showed impaired homotypic and heterotypic gap junction function, but not Cx43.

Connexins form intercellular communication channels, known as gap junctions (GJs), found throughout different tissues and organs. Mutations in genes encoding connexins are found to be linked to various inherited diseases, but the molecular and structural mechanisms are not fully clear. The Arg76 (R76) residue in Cx50 or the equivalent residue in other connexins is fully conserved across the entire connexin family and is a hot spot for five connexin-linked inherited diseases, including congenital cataract, oculodentodigital dysplasia, and cardiac arrhythmias. To better understand the molecular and cellular mechanism of dysfunction caused by mutations of this residue, we examined the functional status and properties of GJs containing R76 mutations in Cx50 (R76H/C), Cx43 (R76H/S/C), and Cx45 (R75H) with an emphasis on heterotypic GJs in connexin-deficient model cells. All tested mutants showed a significantly decreased coupling% and conductance, except for Cx43 R76H/S. These connexin mutants also showed reduced coupling% and conductance when paired with a docking compatible connexin (Cx50/Cx46, Cx45/Cx43), and except for Cx43 R76H/S/C, all formed functional GJs with Cx45. Our homology structure models indicated that mutations of R76 or the equivalent residue in these GJs led to a loss of intra- and/or inter-connexin non-covalent interactions (salt bridges) at the sidechain of this residue, which could contribute to the observed GJ impairments underlying diseases. It remains unclear why Cx43 GJ could tolerate some variations at this residue. Supported by NSERC.

Computational studies of molecular permeation through large-pore channels.

Connexin hemichannels are a family of highly regulated non-beta-barrel large-pore channels permeable to diverse small molecules. Despite their critical roles in mediating biological signaling, the molecular basis of selective permeation through these pores remains unclear. To bridge the knowledge gap between the structure and function of these large-pore channels, we use two complementary molecular dynamics (MD) simulation techniques, rare-event sampling and non-equilibrium steady-state flux, to compute the free energies and kinetics of molecular permeation through connexins. The link between these macroscopic properties and atomistic details of the permeation process provides valuable information for understanding the selectivity of large-pore channels and how human connexin mutations cause diseases.

Increased Hemichannel Activity Displayed by a Connexin43 Mutation Causing a Familial Connexinopathy Exhibiting Hypotrichosis with Follicular Keratosis and Hyperostosis.

Mutations in the GJA1 gene that encodes connexin43 (Cx43) cause several rare genetic disorders, including diseases affecting the epidermis. Here, we examined the in vitro functional consequences of a Cx43 mutation, Cx43-G38E, linked to a novel human phenotype of hypotrichosis, follicular keratosis and hyperostosis. We found that Cx43-G38E was efficiently translated in Xenopus oocytes and localized to gap junction plaques in transfected HeLa cells. Cx43-G38E formed functional gap junction channels with the same efficiency as wild-type Cx43 in Xenopus oocytes, although voltage gating of the gap junction channels was altered. Notably, Cx43-G38E significantly increased membrane current flow through the formation of active hemichannels when compared to wild-type Cx43. These data demonstrate the association of increased hemichannel activity to a connexin mutation linked to a skeletal-cutaneous phenotype, suggesting that augmented hemichannel activity could play a role in skin and skeletal disorders caused by human Cx43 mutations.

Pharmacologic Targeting of the C-Terminus of Heat Shock Protein 90 Improves Neuromuscular Function in Animal Models of Charcot Marie Tooth X1 Disease.

Charcot-Marie-Tooth X1 (CMTX1) disease is an inherited peripheral neuropathy that arises from loss-of-function mutations in the protein connexin 32 (Cx32). CMTX1 currently lacks a pharmacologic approach toward disease management, and we have previously shown that modulating the expression of molecular chaperones using novologue therapy may provide a viable disease-modifying approach to treat metabolic and demyelinating neuropathies. Cemdomespib is an orally bioavailable novologue that manifests neuroprotective activity by modulating the expression of heat shock protein 70 (Hsp70). We examined if 1 to 5 months of daily cemdomespib therapy may improve neuropathic symptoms in three mouse models of CMTX1 (Cx32 deficient (Cx32def), T55I-Cx32def, and R75W-Cx32 mice). Daily drug therapy significantly improved motor nerve conduction velocity (MNCV) and grip strength in all three models, but the compound muscle action potential was only improved in Cx32def mice. Drug efficacy required Hsp70 as improvements in MNCV, and the grip strength was abrogated in Cx32def × Hsp70 knockout mice. Five months of novologue therapy was associated with improved neuromuscular junction morphology, femoral motor nerve myelination, reduction in foamy macrophages, and a decrease in Schwann cell c-jun levels. To determine if c-jun may be downstream of Hsp70 and necessary for drug efficacy, c-jun expression was specifically deleted in Schwann cells of Cx32def mice. While the deletion of c-jun worsened the neuropathy, cemdomespib therapy remained effective in improving MNCV and grip strength. Our data show that cemdomespib therapy improves CMTX1-linked neuropathy in an Hsp70-dependent but a c-jun-independent manner and without regard to the nature of the underlying Cx32 mutation.

Expression of KID syndromic mutation Cx26S17F produces hyperactive hemichannels in supporting cells of the organ of Corti.

Some mutations in gap junction protein Connexin 26 (Cx26) lead to syndromic deafness, where hearing impairment is associated with skin disease, like in Keratitis Ichthyosis Deafness (KID) syndrome. This condition has been linked to hyperactivity of connexin hemichannels but this has never been demonstrated in cochlear tissue. Moreover, some KID mutants, like Cx26S17F, form hyperactive HCs only when co-expressed with other wild-type connexins. In this work, we evaluated the functional consequences of expressing a KID syndromic mutation, Cx26S17F, in the transgenic mouse cochlea and whether co-expression of Cx26S17F and Cx30 leads to the formation of hyperactive HCs. Indeed, we found that cochlear explants from a constitutive knock-in Cx26S17F mouse or conditional in vitro cochlear expression of Cx26S17F produces hyperactive HCs in supporting cells of the organ of Corti. These conditions also produce loss of hair cells stereocilia. In supporting cells, we found high co-localization between Cx26S17F and Cx30. The functional properties of HCs formed in cells co-expressing Cx26S17F and Cx30 were also studied in oocytes and HeLa cells. Under the recording conditions used in this study Cx26S17F did not form functional HCs and GJCs, but cells co-expressing Cx26S17F and Cx30 present hyperactive HCs insensitive to HCs blockers, Ca2+ and La3+, resulting in more Ca2+ influx and cellular damage. Molecular dynamic analysis of putative heteromeric HC formed by Cx26S17F and Cx30 presents alterations in extracellular Ca2+ binding sites. These results support that in KID syndrome, hyperactive HCs are formed by the interaction between Cx26S17F and Cx30 in supporting cells probably causing damage to hair cells associated to deafness.

SERUM IGM DEFICIENCY ASSOCIATED WITH CONNEXIN MUTATION IN AN 18-YEAR-OLD MALE

<h3>Introduction</h3> Selective IgM deficiency (SIGMD) is characterized by remarkably low serum levels of IgM with normal IgG and IgA levels. These patients clinically present with recurrent infections, autoimmune disorders, and malignancies. While unknown, the proposed mechanisms explain the pathophysiology as an issue due to impaired IgG antibody response. The connexin genes encode for gap junctional proteins where mutations can cause hearing deficits and immune dysregulation. We present an 18-year-old patient with recurrent sinusitis and diagnosed connexin-26 mutation and SIGMD. <h3>Case Description</h3> An 18-year-old male with chronic sinusitis, Marfanoid joint hypermobility syndrome, and sensorineural hearing loss due to connexin-26 deficiency with bilateral cochlear implants. This patient's mutation is a GJB2 deletion located on chromosome 13 which encodes for the connexin-26 protein. The patient experienced recurrent infections, and serum immunoglobulins showed a normal IgA (84 mg/dL; normal: 70-400 mg/dL), IgG (922 mg/dL; normal: 700-1600 mg/dL) and reduced IgM (26 mg/dL; normal: 40-230 mg/dL) levels. The patient was responsive to Mumps, Measles, Rubella, and Diphtheria vaccinations amongst others, consistent with SIGMD diagnoses. Antibody responses to polysaccharide antigens were absent. The leukocyte counts were within normal limits. His parents are connexin-26 deficient carriers, and his older brother was diagnosed with SIGMD. <h3>Discussion</h3> Connexin-26 has been identified with multiple immunological mechanisms. Although mutations of this gene have no direct tie to antibody formation in relation to IgM, the presence of these two pathologies in one patient is intriguing and may suggest a pathophysiologic connection. We describe the first case of connexin mutation with SIGMD in an 18-year-old male.

Loss of fiber cell communication may contribute to the development of cataracts of many different etiologies.

The lens is an avascular organ that is supported by an internal circulation of water and solutes. This circulation is driven by ion pumps, channels and transporters in epithelial cells and by ion channels in fiber cells and is maintained by fiber-fiber and fiber-epithelial cell communication. Gap junctional intercellular channels formed of connexin46 and connexin50 are critical components of this circulation as demonstrated by studies of connexin null mice and connexin mutant mice. Moreover, connexin mutants are one of the most common causes of autosomal dominant congenital cataracts. However, alterations of the lens circulation and coupling between lens fiber cells are much more prevalent, beyond the connexin mutant lenses. Intercellular coupling and levels of connexins are decreased with aging. Gap junction-mediated intercellular communication decreases in mice expressing mutant forms of several different lens proteins and in some mouse models of lens protein damage. These observations suggest that disruption of ionic homeostasis due to reduction of the lens circulation is a common component of the development of many different types of cataracts. The decrease in the lens circulation often reflects low levels of lens fiber cell connexins and/or functional gap junction channels.